Composition of nutrition supplementation for nutritional deficiencies and method of use therefore

ABSTRACT

A nutritional supplement composition for treating nutritional deficiencies caused by a medical condition in subjects is disclosed. The present application further discloses a method of using a nutritional supplements composition for treating a subject with complications resulting from sickle cell anemia. The method comprises administering to a subject an effective amount of the nutritional supplement.

This application is a continuation application of U.S. application Ser.No. 14/936,957, filed Nov. 10, 2015, which is a divisional of U.S.application Ser. No. 14/444,278, filed Jul. 28, 2014, which is acontinuation of U.S. application Ser. No. 13/105,383, filed on May 11,2011, now U.S. Pat. No. 8,840,950, which claims the priority ofProvisional Application No. 61/348,430, filed on May 26, 2010. Theentirety of the aforementioned applications is incorporated herein byreference.

This application was made with government support under certain grantsawarded by the NIH. The government has certain rights in the invention.

FIELD

This application generally relates to the field of a nutritionalsupplement designed to treat targeted nutritional problems caused by amedical condition in subjects; in particular, relates to prevention andtreatment of nutritional deficiencies in sickle cell anemia subjects.

BACKGROUND

Sickle cell disease is an inheritable hematological disorder based on amutation in the β-globin gene of hemoglobin. Upon deoxygenation, thismutated hemoglobin polymerizes and causes a shape change (sickling) ofthe red blood cell. This change in red blood cells leads to obstructionof blood vessels causing a wide variety of complications such as stroke,pulmonary hypertension, end-organ disease and death.

This deformation damages the membrane of subjects' red blood cells andmakes the average life of the red blood cells in the range of 10 to 20days as opposed to 120 days for normal individuals. As a result,subjects suffer from chronic anemia. These damaged red blood cells havea tendency to adhere to the endothelial cells of the blood vessel,neutrophils and platelets, and thus, obstruct blood flow causingfrequent painful episodes called “sickle cell crisis,” damaging organsand impairing bone joints.

In addition to the fatal or potentially fatal complications, there areserious nonfatal complications of sickle cell disease such as pain. Theseverity of the pain may vary, but normally requires some form ofmedical attention, and hospitalization may be necessary. Chronicinflammation is one of the complications of subjects with sickle celldisease and studies from our laboratory show that both circulating CRPand IL-6 are elevated in steady-state children with sickle cell anemia.

In the U.S. alone, approximately 70,000-100,000 people suffer fromsickle cell disease. Sickle cell disease is estimated to affect one ofevery 1,300 infants in the general population, and one of every 500 ofAfrican descent. Currently, there is no cure for sickle cell disease.The disease is chronic and lifelong. Life expectancy is typicallyshortened.

Previous patents involving methods of treating sickle cell disease havebeen focused mainly on the effects of the sickled red cells, as the onlysymptom of the disease. Traditional treatment includes vitamin andmineral supplements directed at normalizing erythropoiesis, increasingHbF production, maintaining hydration of the red cells and whole bodyand blood transfusions to supply normal, red cells.

For example, U.S. Pat. No. 4,945,083, issued Jul. 31, 1990 to ChristianJansen, Jr. describes a method for treating or preventingmacrocytic-megaloblastic anemia with multifactor vitamin formulations.Other combination therapies for sickle cell anemia (HbSS) withformulations that include vitamins are described in U.S. Pat. No.5,626,884, issued May 6, 1997 to Lockett, and U.S. Pat. No. 7,214,709,issued May 8, 2007 to Kimoto et al. Both describe formulations includingascorbic acid (vitamin C).

The only cure for this disease is bone marrow transplant, which is notwidely available. Currently, the only medication, which seems to havesome efficacy, is an oral administration of hydroxyurea. This compoundincreases the cellular content of fetal hemoglobin (HbF), which does notpolymerize at low oxygen concentration like HbS. However, hydroxyureahas some negative side effects, such as bone marrow suppression, and alife-long administration may not be recommended.

Accordingly, there is a need in the art for the treatment of sickle celldisease or the complications associated therewith. The present inventionfulfills these needs and further provides other related advantages.

SUMMARY

One aspect of the present invention relates to a method for treatingconditions associated with fast energy metabolism or high energyrequirement. The method includes administering to a subject in need ofsuch treatment a daily nutritional supplement having total calories ofabout 700-980 kcal, wherein about 10-20% of the total calories arederived from protein, about 25-40% of the total calories are derivedfrom fat, and about 45-65% of the total calories are derived fromcarbohydrate.

In one embodiment, the conditions associated with abnormally slow energymetabolism include malnutrition, anorexia, cancers, AIDS and aging.

In another embodiment, the conditions associated with high energyrequirement include sickle cell anemia, pregnancy, lactation, growth,exercise, cancers, infectious diseases and recovery from surgical andother injuries.

In a related embodiment, the condition associated with abnormally highenergy requirement is sickle cell anemia.

In another embodiment, the nutritional supplement is administered orallyin the form of a snack. In a related embodiment, the nutritionalsupplement is administered orally as the last snack before sleeping. Inanother related embodiment, the nutritional supplement is administeredas snacks after each meal.

Another aspect of the present invention relates to a nutritionalsupplement to normal diet for treating conditions associated withabnormally slow energy metabolism or high energy requirement. Thenutritional supplement contains protein in an amount that provides about10-20% of the total calories, fat in an amount that provides about25-40% of the total calories, and carbohydrate that provides about45-65% of the total calories.

In a related embodiment, the nutritional supplement contains about 14%protein energy (i.e., about 24-34 grams of protein for a 700-980 kcaldaily dose), about 32% of fat energy (i.e., about 25-35 grains of fatfor a 700-980 kcal daily dose) and about 55% carbohydrate energy (i.e.,about 96-135 grams carbohydrates fat for a 700-980 kcal daily dose).

In another embodiment, the nutritional supplement further includes atleast one food grade amino acid selected from the group consisting ofarginine, histidine, leucine, valine, cysteine and glutamine.

In a related embodiment, the arginine, histidine, leucine, valine,cysteine and glutamine are included in the dose of 8-14 mg/kg bodyweight/day for adults and 22-44 mg/kg body weight/day for children.

In another embodiment, the nutritional supplement further containsS-ally cysteines, S-allylmercapto cysteine and fructosyl arginine. In arelated embodiment, the supplement contains a garlic extract containingS-allyl cysteines, S-allylmercapto cysteine and fractosyl arginine.

In another embodiment, the nutritional supplement further contains oneor more antioxidants. Suitable antioxidants for administration with thepresent composition include, but are not limited to, Vitamin A, VitaminC, Vitamin E, P-carotene, selenium and other conventional antioxidants.

In a related embodiment, antioxidants are Vitamin C and Vitamin E.

In another embodiment, the nutritional supplement further contains oneor more of the following: Vitamin A 8,250-250,000 I.U., Vitamin B-125-1000 mg, Vitamin B-2 25-1000 mg, Vitamin B-6 25-1000 mg, Vitamin B-1225-1000 mcg, Vitamin C 25-1000 mg, Vitamin D 100-4000 I.U., Vitamin E25-1000 I.U., Niacinamide 25-1000 mg, Para-aminobenzoic acid (PABA)25-1000 mg, Pantothenic Acid 25-1000 mg, Choline Bitartrate 25-1000 mg,Inositol 25-1000 mg, Rutin 8.25-250 mg, Citrus Bioflavonoid Complex8.25-250 mg, Betaine Hydrochloride 8.25-250 mg, Hesperidin Complex1.25-50 mg, Folic Acid 100-4000 mcg, Biotin 25-1000 mcg, Calcium 10-400mg, Iron 8.25-250 mg, Magnesium 5-100 mg, Zinc 5-100 mg, Potassium3,75-150 mg, Manganese 1.5-60 mg, Iodine 37.5-1500 mcg, Chromium3.75-150 meg, and Selenium 2.5-100 mcg.

In another embodiment, the nutritional supplement further contains oneor more of L-lysine-L-phenylalanine, L-lysine-L-tyrosine,L-histidine-L-lysine-L-tyrosine-L-histidine, in particularL-lysine-L-phenylalanine, and salts thereof at a per diem dose withinthe range of from 10 to 150 mg/kg, preferably from 20 to 80 mg/kg.

In another embodiment, the nutritional supplement further containsthiocyanates in an amount of 100-500 mg. In a related embodiment, thethiocyanate is mixed with Vitamin B6 at a weight ratio of about 20:1.

In another embodiment, the nutritional supplement is a protein/energydense, low bulk biscuit further containing pharmaceutically acceptablecarriers, diluents and/or adjuvants.

Another aspect of the present invention relates to a kit comprising anutritional supplement to normal diet for treating conditions associatedwith abnormally slow energy metabolism or high energy requirement, andan instruction on how to use the nutritional supplement. The nutritionalsupplement contains protein in an amount that provides about 10-20% ofthe total calories, fat in an amount that provides about 25-40% of thetotal calories, and carbohydrate that provides about 45-65% of the totalcalories.

In one embodiment, the nutritional supplement is formulated in aready-to dispense form.

In another embodiment, the nutritional supplement is formulated in aready-to dispense single-dose form designed for complete consumption asa snack.

In another embodiment, the nutritional supplement is formulated in aready-to dispense three-dose form designed as a snack after each meal.

In another embodiment, the nutritional supplement is formulated forcomplete consumption as a two-pack snack to be taken in the morning andevening.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a diagram showing that the average age was not different forthe control children versus those with sickle cell anemia.

FIG. 2 is a diagram showing that the average height was not differentfor the control children versus those with sickle cell anemia.

FIG. 3 is a diagram showing that children with sickle cell anemia havesignificantly lower weight compared with age matched healthy controls.

FIG. 4 is a diagram showing that sickle cell children had significantlylower fat free mass compared with controls.

FIG. 5 is a diagram showing that sickle cell children had significantlyhigher resting energy expenditure (REE) for amount of fat free masscompared with controls.

FIG. 6 is a diagram showing that FFM increased by 11.0% from 2 to 4months for the supplemented group versus a slight decrease (1.0%) forthe placebo group. The fluctuations in the number of participants mayhave contributed to the changes observed between baseline and 2 month.

FIG. 7 is a diagram showing that percentage body fat was lower atbaseline for the supplemented vs. placebo group, and did not changesignificantly over time; indicating that there was no accumulation offat calories due to increased calorie consumption from the supplement.

FIG. 8 is a diagram showing that the supplemented group showed a largerdecrease (15.1% vs 9.5%) in resting energy expenditure normalized forfat free mass (REE/FFM ratio) compared with placebo. This resultrepresents an increase in FFM, but also a decrease in gross REE value.

FIG. 9 is a diagram showing that the supplemented group showed a 42.4%decrease in dROM, an index of oxidative stress, compared with a 35.7%for the placebo group.

FIG. 10 is a diagram showing a 34.9% increase in plasma glutamine levelfor the supplemented group vs. a net decrease of 2.9% for the placebogroup. Glutamine is useful as a neurotransmitter and a source of energyfor the intestinal cells. It also has been shown to reduce REE in sicklecell children.

FIG. 11 is a diagram showing that circulating histidine levels increasedby 15.2% for the supplemented vs. 17.8 for the placebo group, suggestingno group difference. Histidine is an essential amino acid needed forgrowth and repair.

FIG. 12 is a diagram showing that plasma citrulline levels increased by84.7% for supplemented vs. 18.6% for the placebo groups. Citrulline isessential for vascular and muscle strengthening functions and is anintermediate of the urea cycle pathway.

FIG. 13 is a diagram showing that plasma arginine levels increased by42.7% for the supplemented vs. 6.9% for placebo groups. Like citrulline,arginine is needed to generate nitric oxide (NO) needed for maintainingnormal vessel tone among other essential functions and is a product inthe urea cycle pathway.

FIG. 14 is a diagram showing that plasma valine levels increased by11.2% for the supplemented group, vs. a 2.2% reduction for the placebogroup. Valine is required for normal muscle and energy metabolism,immune function and reducing muscle inflammation. It is one of thebranched chain essential amino acids.

FIG. 15 is a diagram showing that plasma ornithine levels were increasedby 8.4% for the supplemented group vs. a decrease of 17.9 for theplacebo group. Ornithine is an essential intermediate in the urea cycleand is one of the products of hydrolysis of arginine (by arginase) tourea.

FIG. 16 is a diagram showing that the supplemented group showed a 152%increase in cysteine levels vs. a 43.8% decrease for the placebo group.Cysteine is essential for the synthesis of cystine, glutathione, andmany metaloprotein enzymes and transport molecules.

FIG. 17 is a diagram showing that plasma cystine increased for bothgroups, for the supplemented group cystine increased 26% vs. 8% for theplacebo group. Cystine is an amino acid needed for the synthesis ofstructural proteins such as hair. Its level tends to mirror the levelsof its precursor cysteine.

FIG. 18 is a diagram showing that the supplemented group showed anincreased in the circulating levels of oxidized glutathione (GSSG) by154% vs. no change in plasma levels for the placebo group, over 2months. The decrease at 4 months in the supplemented group may be due tonumber of participants at that time.

FIG. 19 is a diagram showing that glutathione levels increased by 10.4%for the supplemented group vs. a 2.8% increase for the placebo group.Glutathione is an antioxidant needed to reduce the level of hemolysisand other oxidative tissue damage seen in sickle cell anemia.

DETAILED DESCRIPTION

The following detailed description is presented to enable any personskilled in the art to make and use the invention. For purposes ofexplanation, specific nomenclature is set forth to provide a thoroughunderstanding of the present invention. However, it will be apparent toone skilled in the art that these specific details are not required topractice the invention. Descriptions of specific applications areprovided only as representative examples. The present invention is notintended to be limited to the embodiments shown, but is to be accordedthe widest possible scope consistent with the principles and featuresdisclosed herein.

Cogent evidence has long shown that sickle cell patients have higherthan normal metabolic requirements for protein, energy and specificamino acids, particularly those amino acids associated with growth,repair, energy expenditure and more recently, antioxidant andinflammatory status. The present invention provides a supplement ofincreased energy and protein to address the malnutrition and poor immunestatus, plus include increased levels of key amino acids required forwhole body growth and development, which are low in sickle cell patientsbecause they are diverted toward meeting the increased requirement forsynthesis of red cells and inflammatory proteins.

One aspect of the present invention relates to a method for treatingconditions associated with abnormally slow energy metabolism or highenergy requirement. The method includes administering to a subject inneed of such treatment a daily nutritional supplement having totalcalories of about 700-980 kcal, wherein about 10-20% of the totalcalories are derived from protein, about 25-40% of the total caloriesare derived from fat, and about 45-65% of the total calories are derivedfrom carbohydrate.

Conditions associated with abnormally slow energy metabolism include,but are not limited to, under nutrition such as caused by food shortage(famine) and diseases characterized by cechexia, e.g., anorexia,cancers, AIDS, other infectious diseases and aging. Conditionsassociated with high energy requirements and/or increased nutritionalneeds include, but are not limited to sickle cell anemia, pregnancy,lactation, growth and recovery from surgical and other injury. The useof the present invention also extends to many other conditions withsimilar nutritional requirements. In one embodiment, the conditionassociated with abnormally fast energy metabolism is sickle cell anemia.

Resting energy expenditure is increased in children and adults withsickle cell anemia by 16 to 20% (Badaloo et al., Clinical Science 77:93-97, 1989; Salman et al., Pediatr Res 40: 34-40, 1996; and Hibbert etal., J Pediatr Gastroenterol Nutr 43: 680-687, 2006).

Resting energy expenditure is approximately 70% of total energyexpenditure. An additional 20% of the estimated total energy requirementwould be 350 and 490 kcal for children and adults, respectively. Theenergy supplement provides an additional 40% of the usual energyrequirement for each individual (about 700 to 980 kcal per day). Thisestimation accounts for energy and protein losses during digestion andabsorption, i.e. efficiency of utilization, and covers any initialunderestimate. Adjustment for the initial estimation can be madefollowing the pilot intervention and during the intervention on anindividual basis. It has been demonstrated that a higher than normalprotein diet for mice (35% versus 20% of energy from proteinrespectively) increased rate of weight gain in weanling ss mice andreduced circulating inflammatory proteins C-reactive protein (CRP) andinterleukin-6 (IL-6) (Archer et al., J Nutr 138: 1148-1152, 2008).Indeed, chronic inflammation is one of the complications of patientswith sickle cell disease and studies show that both circulating CRP andIL-6 are elevated in steady-state children with sickle cell anemia(Hibbert et al., Exptl Bioi Med 230: 68-74, 2005). A dietary supplementmay alleviate some complications of sickle cell anemia.

In certain embodiments, the supplement is a balanced formula providingthe additional energy requirement for each individual as a foodsupplement with 700-980 kcal energy supplied by 10-20% protein derivedenergy, 25-40% fat derived energy, and 45-65% carbohydrate derivedenergy.

In one embodiment, the supplement contains 14% protein derived energy,32% fat derived energy and 55% carbohydrate derived energy. This wouldamount to an additional 24-34 grams protein, 96-135 grams carbohydrateand 25-35 grams fat per day, respectively, for the 700-980 kcal that isadministered via the supplement.

Suitable protein sources include animal proteins and plant proteins.Non-limiting examples include, but are not limited to, whey protein, soyprotein, milk protein, egg protein, casein, peanut flour, nut meats, andcombinations thereof Soy protein is extracted from soybean and isconsidered to be an economical protein source. The most popular types ofsoy protein are soy protein isolates and soy protein concentrates. Soyprotein isolates are highly digestible and a good source of amino acidsand isoflavones. In addition, they are low in fat, calories, andcholesterol. For vegetarians, this is a primary source of protein. Wheyprotein is derived from whey, which is a by product obtained from makingcheese. Functionally, whey proteins are highly soluble even under acidicconditions. There are primarily two forms of whey protein, whey proteinisolate and whey protein concentrate. Both are extremely high qualityproteins that are highly digestible. However, whey protein isolate issomewhat superior because it is higher in protein and has lower fat,lactose, and flavor levels than whey protein concentrate. Casein is theprimary protein found in milk protein, which is about 80% casein and 20%whey protein. Casein includes caseinates, which are available in threemain types, sodium, calcium, and potassium. Spray dried egg whites areused in some “egg and milk” protein powder mixes.

Suitable fat sources include, but are not limited to, chocolate, peanutbutter, fat substitutes, vegetable fats, tropical fats, animal fats,dairy/milk and combinations thereof.

Suitable carbohydrate sources include, but are not limited to, starch,sugar, gels, syrups, honey, molasses, rice syrups, and combinationsthereof.

In another embodiment, the supplement further contains S-allylcysteines, S-allylmercapto cysteine and -fructosyl arginine. In arelated embodiment, the supplement contains a garlic extract containingS-allyl cysteines, S-allylmercapto cysteine and fructosyl arginine.

In another embodiment, the supplement further contains one or moreantioxidants. Suitable antioxidants for administration with the presentcomposition include, but are not limited to, Vitamin A, Vitamin C,Vitamin E, (3-carotene, selenium and other conventional antioxidants.Preferred among the antioxidants are Vitamin C and Vitamin E. In arelated embodiment, antioxidants are Vitamin C and Vitamin E.

In another embodiment, the nutritional supplement further contains oneor more of the following: Vitamin A 8,250-250,000 I.U., Vitamin B-125-1000 mg, Vitamin B-2 25-1000 mg, Vitamin B-6 25-1000 mg, Vitamin.B-12 25-1000 mcg, Vitamin C 25-1000 mg, Vitamin D 100-4000 I.U., VitaminB 25-1000 I.U., Niacinamide 25-1000 mg, Para-aminobenzoic acid (PABA)25-1000 mg, Pantothenic Acid 2.5-1000 mg, Choline Bitartrate 25-1000 mg,Inositol 25-1000 mg, Rutin 8.25-250 mg, Citrus Bioflavonoid Complex8.25-250 mg, Betaine Hydrochloride 8.25-250 mg, Hesperidin Complex1.25-50 mg, Folic Acid 100-4000 mcg, Biotin 25-1000 mcg, Calcium 10-400mg, Iron 8.25-250 mg, Magnesium 5-100 mg, Zinc 5-100 mg, Potassium3.75-150 mg, Manganese 1.5-60 mg, Iodine 37.5-1.500 mcg, Chromium3.75-150 meg, and Selenium 2.5-100 mcg.

Amino acids L-arginine, histidine, leucine, valine, cysteine andglutamine known to be in greater demand for sickle cell anemia patients,is added to the supplement at the requirement for normal healthychildren 1.0 to 12 years (22-44 mg/kg/d.) and for adults (8-14 mg/kg/d),i.e. a 50 kg person would receive 6 amino acids a 7 8 mg/kg each for atotal of 2.4 grams of supplemental amino acid/day. The added amino acidsare food grade, purchased from Ajinomoto Aminoscience LLC (Raleigh,N.C.).

Vanillin food flavor is added to the supplement and urinary vanillicacid, the major excretory metabolite of vanillin, is measured as abiochemical marker of compliance with supplement consumption (Sayavongsaet al., e-J Clin Nutr Metabolism 2: e134-e137, 2007), in addition totraditional compliance monitoring.

In one embodiment, the supplement of the present invention is given tochildren and adults with a confirmed diagnosis of sickle cell anemia,who are underweight (having a body mass index of 17 or less for childrenand 20 or less for adults) and who have not been treated with frequentblood transfusions or hydroxyurea. The supplement is given as anutritional supplement to the normal diet, consumed daily as the lastsnack prior to bedtime. It supplies an additional 40% of energy(calories) to the normal daily individual energy consumption.

Administration

The supplement is in the form of a protein/energy dense, low bulkcookie. In one embodiment, the nutrition supplement is administeredorally as a snack or snacks. The required daily amount (700-980 kcal perday) may be administered in single dose as the last snack beforesleeping, or in two or more doses during the day (e.g., morning andafternoon, or after each meal).

If the formula is designed for complete consumption as the last snackbefore sleeping, it is imperative that it should supply extra caloriesand protein without bulk. The supplement formulation may be adapted foralternative methods of administration. Examples (include, but are notlimited to): liquid formulations (milk shake, energy drink, infusions),candy bar, cookies, etc.

Kits

The invention also encompasses a kit comprising a nutritional supplementto normal diet for treating conditions associated with abnormally slowenergy metabolism or high energy requirement, and an instruction on howto use the nutritional supplement. The nutritional supplement containsprotein in an amount that provides about 10-20% of the total calories,fat in an amount that provides about 2540% of the total calories, andcarbohydrate that provides about 45-65% of the total calories. In oneembodiment, the nutritional supplement is formulated in aready-to-dispense form.

The present invention is further illustrated by the following examplesthat should not be construed as limiting. The contents of allreferences, patents, and published patent applications cited throughoutthis application, as well as the Figures and Tables, are incorporatedherein by reference.

EXAMPLE 1 Nutritional Supplement Study

Twelve children (SS) with sickle cell anemia (SCA)) at ages between 6-12were randomly allocated into the placebo (5) group and supplement (7)group, and were given either a placebo cookie (for placebo group) or thesupplement cookie (for supplement group). Normal children without SCA,but similar age served as controls (AA, n=9). Information onanthropometric, body composition, resting energy expenditure, bloodlevels of amino acids, and production of reactive oxygen species andlevel of consumption of natural antioxidants were collected. Dataanalysis was done on an intent-to-treat basis (gold standard), meaningthat irrespective of how far each participant went in the study, allparticipants were included in the analysis of their allocated group. Thenumbers of participants (n) during the study are as follows:

Baseline; n=9 for AA, n=5 for placebo and 7 for supplement SCA groupsSCA intervention periods

2 weeks; n=5 for placebo and 3 for supplement

1 month; n=5 for placebo and 3 for supplement

2 month; n=4 for placebo and 3 for supplement

3 month; n=2 for placebo and 3 for supplement

4 month; n=3 for placebo and 2 for supplement.

At baseline the AA and SCA groups were similar in Age (9.4 vs. 9.1, FIG.1), with moderate difference in height (143 cm vs. 130.6 cm, FIG. 2) buttheir weight was markedly different (40.5 kg vs. 25.2 kg, FIG. 3) andthus their body mass index (BMI) (20 vs. 14.7), indicating a subnormalnutritional status for age. The children with sickle cell anemia alsoshowed a lower fat free mass (FFM) or lean body mass (16.7 kg vs. 27.6kg, FIG. 4), but a higher resting energy expenditure (REE) for theamount of FFM as indicated by a higher REE to FFM ratio (FIG. 5). Thechildren with sickle cell anemia were then given either placebo orsupplement cookie for 3-4 months and the results collected aresummarized below:

Anthropometry, Body Composition and Oxidant Stress Level

There was no change in BMI for either the placebo or supplement groupfrom baseline to 4 months. As shown in FIG. 6, the fat free mass (FFM)increased by 4.4% for placebo and decreased by 0.3% for the supplementgroups when comparing the baselines with 4 months measurements. Butfurther analysis from 2 months to 4 months showed an 11% increase forthe supplement group as opposed to only 0.8% for the placebo group.

As shown in FIG. 7, the % body fat for the children with SCA onsupplement was lower than that for those on placebo. The graph showedthat it was lower (17.3% vs. 23.1%) at baseline and stayed so even after4 months on the supplement; indicating that the additional nutrient andenergy provided is being used up and not allowed to accumulate andcreate unnecessary and/or unhealthy weight gain. During this feedingperiod, there was a 0.3% gain in weight from baseline among thesupplement group as opposed to a 0.5% decrease in weight for the placebogroup.

The average resting energy expenditure (REE) for the children onsupplement was higher (977.7 cal vs. 898 cal) than of those on placeboat baseline. By 4 months, the resting energy expenditure has decreasedby 14.2% for the supplement group compared with 5.5% for those onplacebo. FIG. 8 shows a 15.5% decrease in the ratio of REE to FFM forthe supplement group compared with 9.5% for the group on placebo. Notethat under normal circumstance, FFM is one of the major determinants ofREE. In this case despite the fact that there was no increase in REE(probably because it was already too high for the amount of FFM at thebaseline) the increase in the FFM earlier noted meant a decrease in theREE to FFM ratio towards normal for the amount of FFM.

There was also a decrease (42.4% vs. 35.7%) in the level oxidant stressfrom baseline for the supplement group compared with the placebo group.Oxidant stress here measured as the concentration of reactive oxygenspecies (dROMS).

Plasma Amino Acids Levels

The plasma levels of some of the amino acids measured also improved forthe supplement group more than the placebo. These amino acids are thosewe supplemented and are known to be significantly lower in SCA patients,as indicated by the baseline values (except cysteine and cystine) whenone compares both placebo and supplement values to the controls (AA).

After 3-4 months of supplementation (a short time for a dietarysupplementation study), there was a 34.9% increase in plasma glutaminelevel for the group on supplement cookie compared with a 2.9% decreaseamong the placebo group over the same time period (FIG. 10). Similarlythe histidine and citrulline levels increased by 15.2% and 84.7% for thegroup on supplement compared with 17.8% and 18.6% increase respectivelyfor the placebo group (FIGS. 11 and 12). Arginine has been shown to bedeficient albeit very much needed in SCA patients. At baseline theplasma arginine level was higher for the placebo group compared with thesupplement group. But by the 4 months after supplementation with thecookie, the serum arginine level for the group on supplement hasincreased by 42.7% compared with 6.9% for the group on placebo (FIG.13). Also plasma levels of valine, ornithine and cysteine (needed forthe synthesis of glutathione) were higher in the group on supplementcompared with the group on placebo at 4 months. Plasma valine levelsincreased by 11.2% for the supplement group, compared with a decrease of2.2% for the placebo group (FIG. 14). Plasma ornithine levels increasedby 8.4% in the supplemented group compared with a decrease of 17.4% inthe placebo group (FIG. 15). For plasma cysteine, despite the higherbaseline levels for the supplement group, by four months, there was a151.9% increase for the group on supplement compared with a 43.8%decrease for the group on placebo (FIG. 16). Similarly, the plasma levelof cysteine rose by 26.0% for the group on supplement compared with 7.8%for the group on placebo (FIG. 17). The plasma levels of oxidizedglutathione (GSSG) were unchanged for the group on supplement comparedwith a 54.2% rise for the group on placebo, the latter indicating ahigher level of oxidative stress than the supplemented group (FIG. 18).The reverse is true for reduced glutathione (GSH) level, which increasedfrom baseline by 10.3% for the group on supplement, compared with a 2.8%decrease for the placebo group (FIG. 19). This is also an indication ofless effective diffusion of reactive oxidant molecules over time by theplacebo group compared with the supplement group, previouslydemonstrated by FIG. 9.

The above description is for the purpose of teaching the person ofordinary skill in the art how to practice the present invention, and itis not intended to detail all those obvious modifications and variationsof it which will become apparent to the skilled worker upon reading thedescription. It is intended, however, that all such obviousmodifications and variations be included within the scope of the presentinvention, which is defined by the following embodiments. Theembodiments are intended to cover the mentioned components and steps inany sequence which is effective to meet the objectives there intended,unless the context specifically indicates the contrary.

What is claimed is:
 1. A method for treating conditions associated withabnormally slow energy metabolism or high energy requirement,comprising: administering to a subject in need of such treatment a dailynutritional supplement having total calories of about 700-980 kcal,wherein about 10-20% of the total calories are derived from protein,about 25-40% of the total calories are derived from fat, and about45-65% of the total calories are derived from carbohydrate.
 2. Themethod of claim 1, wherein the conditions associated with abnormallyslow energy metabolism include malnutrition, anorexia, cancers, AIDS andaging.
 3. The method of claim 1, wherein the conditions associated withhigh energy requirement include sickle cell anemia, pregnancy,lactation, growth, exercise, infectious diseases and recovery fromsurgical and other injuries.
 4. The method of claim 3, wherein thecondition associated with high energy requirement is sickle cell anemia.5. The method of claim 1, wherein the nutritional supplement isadministered orally in the form of a snack.
 6. The method of claim 5,wherein the nutritional supplement is administered orally as the lastsnack before sleeping.
 7. The method of claim 5, wherein the nutritionalsupplement is administered as snacks after each meal.
 8. A nutritionalsupplement to normal diet for treating conditions associated withabnormally slow energy metabolism or high energy requirement,comprising: protein in an amount that provides about 10-20% of the totalcalories; fat in an amount that provides about 25-40% of the totalcalories; and carbohydrate that provides about 45-65% of the totalcalories.
 9. The nutritional supplement of claim 8, wherein thenutritional supplement comprises: protein in an amount that providesabout 14% of the total calories; fat in an amount that provides about32% of the total calories; and carbohydrate that provides about 54% ofthe total calories.
 10. The nutritional supplement of claim 8, whereinthe nutritional supplement has a total calorie of about 700-980 kcal.11. The nutritional supplement of claim 10, wherein the nutritionalsupplement comprises about 24-34 grams of protein; about 25-35 grams offat; and about 96-135 grams of carbohydrate.
 12. The nutritionalsupplement of claim 8, wherein the nutritional supplement furthercomprises at least one food grade amino acid selected from the groupconsisting of arginine, histidine, leucine, valine, cysteine andglutamine.
 13. The nutritional supplement of claim 12, wherein thenutritional supplement comprises arginine, histidine, leucine, valine,cysteine and glutamine, and wherein each amino acid is provided at a perdiem dose range of 8-14 mg/kg body weight/day.
 14. The nutritionalsupplement of claim 12, wherein the nutritional supplement comprisesarginine, histidine, leucine, valine, cysteine and glutamine, andwherein each amino acid is provided at a per diem dose range of 22-44mg/kg body weight/day.
 15. The nutritional supplement of claim 12,wherein the nutritional supplement further comprises S-allyl cysteines,S-allyhmercapto cysteine and fructosyl arginine.
 16. The nutritionalsupplement of claim 12, wherein the nutritional supplement furthercomprises a garlic extract.
 17. The nutritional supplement of claim 8,wherein the nutritional supplement further comprises one or moreantioxidants.
 18. The nutritional supplement of claim 17, wherein theone or more antioxidants is selected from the group consisting ofVitamin A, Vitamin C, Vitamin E, β-carotene and selenium.
 19. Thenutritional supplement of claim 17, wherein the one or more antioxidantscomprise Vitamin C and Vitamin E.
 20. The nutritional supplement ofclaim 8, further comprising one or more components selected from thegroup consisting of: Vitamin A 8,250-250,000 I.U., Vitamin B-1 25-1000mg, Vitamin B-2 25-1000 mg, Vitamin B-6 25-1000 mg, Vitamin B-12 25-1000mcg, Vitamin C 25-1000 mg, Vitamin D 100-4000 I.U., Vitamin E 25-1000I.U., Niacinamide 25-1000 mg, Paraaminobenzoic acid (PABA) 25-1000 mg,Pantothenic Acid 25-1000 mg, Choline Bitartrate 25-1000 mg, Inositol25-1000 mg, Rutin 8.25-250 mg, Citrus Bioflavonoid Complex 8.25-250 mg,Betaine Hydrochloride 8.25-250 mg, Hesperidin Complex 1.25-50 mg, FolicAcid 100-4000 mcg, Biotin 25-1000 mcg, Calcium 10-400 mg, Iron 8.25-250mg, Magnesium 5-100 mg, Zinc 5-100 mg, Potassium 3.75-150 mg, Manganese1.5-60 mg, Iodine 37,5-1500 meg, Chromium 3.75-150 mcg, and Selenium2.5-100 mcg.
 21. The nutritional supplement of claim 20, furthercomprising one or more component selected from the group consisting ofL-lysine-L-phenylalanine, L-lysine-L-tyrosine,L-histidine-L-lysine-L-tyrosine-L-histidine, and salts thereof at a doserange of 10-150 mg/kg/day.
 22. The nutritional supplement of claim 20,further comprising L-lysine-L-phenylalanine or salts thereof at a doserange of 20-80 mg/kg/day.
 23. The nutritional supplement of claim 8,further comprising thiocyanates in an amount of 100-500 mg.
 24. Thenutritional supplement of claim 23, wherein the thiocyanate is mixedwith Vitamin B6 at a weight ratio of about 20:1.
 25. The nutritionalsupplement of claim 8, wherein the nutritional supplement is formulatedin a ready-to-dispense single-dose form designed for completeconsumption as a snack.
 26. The nutritional supplement of claim 8,wherein the nutritional supplement is formulated in a ready-to-dispensethree-dose form designed as a snack after each meal.
 27. The nutritionalsupplement of claim 8, wherein the nutritional supplement is formulatedfor complete consumption as a two-pack snack to be taken in the morningand evening.